Methods for onapristone synthesis dehydration and deprotection
Methods and systems for making onapristone (ONA) using acidic hydrolysis and dehydration with sulfuric acid in an alcoholic solution are provided.
1. A method of making onapristone comprising:
reacting the compound of Formula I:
with sulfuric acid in a solution comprising pyridine and a solvent to deprotect and dehydrate the compound of Formula I;
maintaining the reaction temperature below about 60° C.;
neutralizing the reaction with an inorganic base to form a solution; and
extracting the compound of Formula II
from the solution.
2. The method of claim 1 , wherein the sulfuric acid is diluted up to 80% with water.
3. The method of claim 2 , wherein the sulfuric acid is diluted from 30 to 60% with water.
4. The method of claim 3 , wherein the sulfuric acid is diluted with 50% water.
5. The method of claim 1 , wherein the solvent is selected form the group consisting of methanol, ethanol, acetone, n-propanol and isopropanol.
6. The method of claim 5 , wherein the solvent is methanol.
7. The method of claim 1 , wherein the temperature is maintained between about −50 to about 60° C.
8. The method of claim 7 , wherein the temperature is maintained between about −10 and 30° C.
9. The method of claim 8 , wherein the temperature is maintained from about 0 to about 15° C.
10. The method of claim 1 , wherein the inorganic base is selected from the group consisting of sodium hydrogen carbonate, sodium phosphate or ammonia.
11. The method of claim 10 , wherein the inorganic base is ammonia with a concentration between about 5 and 30%.
12. The method of claim 11 , wherein the inorganic base is 30% ammonia.
13. The method of claim 1 , wherein the reaction with the inorganic base is performed at a temperature from about 0 to about 30° C.
14. The method of claim 13 , wherein the reaction with the inorganic base is performed at a temperature from about 0 to about 15° C.
15. The method of claim 1 , wherein extraction of the compound of Formula II is performed with ethyl acetate.
16. The method of claim 1 , wherein extraction of the compound of Formula II is performed by crystallization.
17. The method of claim 1 , further comprising concentrating the solution.
18. The method of claim 17 , wherein the solution is concentrated by vacuum distillation.
19. The method of claim 1 , wherein the volume ratio of pyridine to the solvent is in a range of about 1:0.001 to about 1:0.03.
20. The method of claim 1 , wherein the method further comprises reacting at least 1 kg of the compound of Formula I.
21. The method of claim 1 , wherein the method provides a yield of about 80%.
22. The method of claim 1 , wherein the method provides onapristone at a purity of about 88.9%.